tbuckley/cabot-search huggingface dataset:
Abstract 2216: Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women
Authors: Md. Mustafizur Rahman, Md. Mahmudul Kabir, Md. Abdur Rahman, Amir Hossain, Md. Golam Hossain
Journal: Cancer Research (2022)

Abstract Background and aim: Exonuclease 1 (EXO1) is an essential member of the RAD2 nuclease family which is involved in mismatch repair system and contributes to the maintenance of genomic stability, modulation of DNA recombination and cell cycle arrest mediation. Potential polymorphism in EXO1 may have the ability to control cancer risks by influencing the repair activity. K589E (rs1047840) is a potentially functional polymorphism in EXO1 gene and we hypothesized that it might be associated with risk of breast cancer in Bangladesh. Method: We designed a case-control study consisting of 184 subjects with breast cancer and 200 healthy controls to identify the effect of K589E polymorphism on breast cancer susceptibility and clinicopathological features in Bangladeshi women. Genotype determination was performed by PCR-RFLP method. Results: After the adjustment of age and weight, a significant association was found between EXO1 K589E alleles and genotypes and risk of breast cancer. The frequencies of the three genotypes G/G, G/A, and A/A were 49, 42, and 9% in cases whereas 69, 27.5, and 3.5% in controls, respectively. The heterozygote G/A genotype and combined G/A+A/A genotypes showed 2.12-fold (OR=2.12, 95% CI=1.3733 - 3.2822 p=0.0007) and 2.27-fold (OR=2.27, 95% CI=1.5001 - 3.4493, p=0.0001) increased risk of breast cancer, respectively when compared with homozygous G/G genotypes. The variant A allele also was associated with increased risk of breast cancer (OR= 3.46, 95% CI=1.3720 - 8.7571, p=0.0086). Analysis of clinicopathological characteristics and genotype distribution also showed a significant correlation. Conclusion: Our results revealed that EXO1 K589E polymorphism could be a potential predisposing risk factor in genetic susceptibility to breast cancer in Bangladesh. Citation Format: Md. Mustafizur Rahman, Md. Mahmudul Kabir, Md. Abdur Rahman, Amir Hossain, Md. Golam Hossain. Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2216.
Performance of Cervical Screening a Decade Following HPV Vaccination: The Costa Rica Vaccine Trial
Authors: Shang-Ying Hu, Aimée R Kreimer, Carolina Porras, Diego Guillén, Mario Alfaro, Teresa M Darragh, Mark H Stoler, Luis F Villegas, Rebecca Ocampo, Ana Cecilia Rodriguez, Mark Schiffman, Sabrina H Tsang, Douglas R Lowy, John T Schiller, John Schussler, Wim Quint, Mitchell H Gail, Joshua N Sampson, Allan Hildesheim, Rolando Herrero
Journal: JNCI Journal of the National Cancer Institute (2022)

We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age.
Abstract 5350: OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer
Authors: Da-Som Kim, Yun Jung Choi, Young Hoon Sung, Dong Ha Kim, Chae Won Lee, Kyungtaek Lm, Hyeonjeong Lee, Sung-Eun Kim, Sunho Lee, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho
Journal: Cancer Research (2022)

Abstract Osimertinib, an irreversible, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is initially developed to overcome EGFR T790M mutation, and use as standard therapy in patients with advanced non-small cell lung cancer (NSCLC) including EGFR activating mutations as well as EGFR T790M mutation. Despite remarkable efficacy of osimertinib, this therapy is limited by the emergence of acquired resistance, like other EGFR-TKIs. Since epidermal growth factor receptor mutation C797S was founded as the factor of acquired resistance to osimertinib, drug targeting the clinically relevant C797S mutation has not yet been developed. Here, we reported the discovery and preclinical efficacy of OBX02-011, fourth EGFR-TKI targeting overcome EGFR C797S mutation. Compared with the approved EGFR-TKIs, this agent showed potent anticancer effects and the inhibition of EGFR-related signaling in various models including EGFR C797S mutation. Additionally, we evaluated the efficacy of OBX02-011 in transgenic models (EGFRL858R+T790M+C797S), showing the enhanced survival, and inhibition of tumor growth and EGFR activity. Collectively, our data suggest that OBX02-011 may be promising new EGFR-TKI to overcome C797S-mediated resistance in NSCLC. Citation Format: Da-Som Kim, Yun Jung Choi, Young Hoon Sung, Dong Ha Kim, Chae Won Lee, Kyungtaek Lm, Hyeonjeong Lee, Sung-Eun Kim, Sunho Lee, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho. OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5350.
Abstract 4147: CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors
Authors: Kathleen M. Sullivan, Shichang Miao, Huibin Yue, Niky Zhao, Chris Li, Ezra Tai, Karen Ebsworth, Gonzalo Tapia Rico, Paul De Souza, Tom Schall, Penglie Zhang
Journal: Cancer Research (2022)

Abstract Background: The small molecule CCX559 is a novel, highly potent inhibitor of human PD-L1 being developed as an oral treatment for cancer patients. We have previously demonstrated that CCX559 has nanomolar potency and high selectivity for PD-L1; that it enhances primary T cell activation and has anti-tumor efficacy, including the ability to induce complete responses, using in vivo models1. Results: Safety pharmacology studies in preclinical animal species demonstrated pharmacokinetics and an acceptable safety profile for CCX559, which supported the initiation of human trials in patients with advanced tumors. Prior findings from toxicology studies were consistent with immune modulation, including consumptive coagulopathy, increased white blood cell counts, and changes in IL-6 plasma levels. A Phase 1, first in patient, multicenter, open-label, dose-escalation study was initiated, with a starting dose of once-daily (QD) oral dosing at 30 mg. The primary objectives are safety/tolerability, as well pharmacokinetic (PK) assessments aimed at determining a future phase 2 dose. Secondary objectives include pharmacodynamic (PD) assessments of immune cell activation in patient peripheral blood samples, as well as anti-tumor effects. For PK, intensive blood sampling is done on day 1 and day 21 of the first cycle of dosing; additional samples are collected on select days throughout the 21-day treatment cycles. PD analyses are done on selected blood draws as well. The first patient dosed (30 mg QD) showed that the drug was well tolerated with no adverse events reported. Preliminary PK results from this patient revealed CCX559 exposure levels consistent with preclinical predictions. Moreover, PD samples showed elevations in T cell proliferation and activation within the first 15 days, when compared to the predose sample. In conclusion, the preclinical data support clinical development of CCX559. CCX559 shows encouraging initial PK and PD results, and patient enrollment is ongoing in the trial (ACTRN12621001342808). References: 1Chris Li, et al. CCX559 is a potent orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1274. Citation Format: Kathleen M. Sullivan, Shichang Miao, Huibin Yue, Niky Zhao, Chris Li, Ezra Tai, Karen Ebsworth, Gonzalo Tapia Rico, Paul De Souza, Tom Schall, Penglie Zhang. CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4147.
Abstract 3185: Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms
Authors: Kieren D. Marini, Emma C. Champion, Jennifer R. Cochrane, E. Alejandro Sweet-Cordero
Journal: Cancer Research (2022)

Abstract Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remain underexploited. Previously, we validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. From our genetically engineered mouse and our syngeneic modelling of LUAD we have observed that eCNTFR seems to work via two mechanisms, firstly in a tumor intrinsic fashion where it may modulate altered guanosine triphosphate loading, as we see differential effectiveness of eCNTFR-Fc, depending on the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate. Alternatively, eCNTFR also effects the tumor microenvironment and alters the composition of the tumor immune infiltrate, where using single cell genomics we see vast changes to the myeloid compartment, and alteration of the CAF populations, which we have previously shown to be the primary location of CLCF1 expression in mouse LUAD. To further enhance the efficacy of eCNTFR-Fc we have identified potential targets for combination therapy from both the autonomous and non-cell autonomous mechanisms of eCNTFR-Fc. We conclude that eCNTFR-Fc acts through two distinct mechanisms to be a highly effective treatment for Kras mutant LUAD, and combining eCNTER with targets, identified by a rational combination approach, could further enhance its therapeutic potential. Citation Format: Kieren D. Marini, Emma C. Champion, Jennifer R. Cochrane, E. Alejandro Sweet-Cordero. Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3185.
Abstract 5323: Analytic and clinical validation of a new pan-cancer NGS liquid biopsy test for the detection of copy number variations, fusions/exon skipping, somatic variants and indels
Authors: Audrey Audetat, Cherie Tschida, Sarah Kreston, Leisa Jackson, Hestia Mellert, Adam Stephen, Gary A. Pestano
Journal: Cancer Research (2022)

Abstract Liquid biopsy tests are an integral part of the molecular diagnostic workup of patients with multiple cancer types. We have extended validation studies of a new liquid biopsy test panel that uses an amplicon-based targeted next-generation sequencing (NGS) panel with a semiconductor-based system, the Ion GeneStudio S5 Prime. The workflow requires very low input (20 ng) of cell-free nucleic acids extracted from human plasma and has been demonstrated to yield results in less than 72 hours from sample receipt at the laboratory. This report details the analytic performance of the test panel for detecting copy number variations (CNVs), fusions and exon skipping variants in plasma. These data add to previously reported validation data for the detection of somatic nucleotide variants (SNV) and indels [97.7% - 100% concordant with orthogonal droplet digital PCR (ddPCR) tests]. The updated study sample sets included consented clinical and normal healthy, donor specimens, and reference cell lines to detect fusions and exon skipping [HCC78 (ROS1), CRL-5935 (EML4-ALK), KM12 (NTRK1) and HTB-178 (MET exon 14 skipping)], and CNVs [CRL-5928 (HER2 gain), SK-BR-3 (HER2, CDK6, EGFR and MYC gains), HCC-827 (EGFR gain) and CRL-5909 (MET gain)]. The limit of detection (LOD) for fusion/skipping was initially established at a molecular coverage of 42 copies and was then verified by detection of three additional fusion/skipping variants. The LOD for CNVs was initially established at 1.40 fold-change and was then verified with the detection of three additional CNVs. Verification was conducted with specimens near the initially established LOD. In the precision studies, all expected fusion/skipping variants were detected in all runs and all days of testing (n=18/18) generating a hit rate of 100%. An average CV of 20.5% (range 8.7% to 34.8%) for repeatability and 20.8% (range 15.7% to 30.5%) for reproducibility was established. Twenty eight of 29 CNVs were detected, generating a hit rate of 96.6%. An average CV of 1.85% (range 0% to 5.49%) for repeatability and 6.59% (range 1.65% to 9.22%) for reproducibility was established for detected CNVs. We conclude that the validated test panel meets the criteria for being rapid, highly sensitive and specific, and has utility for the reporting of clinically relevant variants of interest in multiple cancer types. Citation Format: Audrey Audetat, Cherie Tschida, Sarah Kreston, Leisa Jackson, Hestia Mellert, Adam Stephen, Gary A. Pestano. Analytic and clinical validation of a new pan-cancer NGS liquid biopsy test for the detection of copy number variations, fusions/exon skipping, somatic variants and indels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5323.
Abstract 2320: Ivermectin suppresses pancreatic cancer via mitochondria dysfunction
Authors: daeun lee, joon seong park, yun sun lee, hyeon woong kang, hyo jung kim
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is an aggressive cancer characterized by high mortality and poor prognosis with survival of less than 5 years when advanced. Several studies showed that the ivermectin has antitumor effects on a variety of cancer cells. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. We found that the anticancer effect of ivermectin in combination with gemcitabine on pancreatic cancer is more effective than gemcitabine alone. Ivermectin-gemcitabine combination inhibited cell proliferation via G1 arrest of the cell cycle, as evidenced by down-regulated cyclin D1 expression through mTOR/STAT3 signaling pathway. In addition, ivermectin-gemcitabine induced apoptosis by ROS generation and reduction of mitochondrial membrane potential (MMP), and blocked mitophagy. In vivo experiments also confirmed that ivermectin-gemcitabine groups significantly suppressed the tumor growth of pancreatic cancer compared with gemcitabine alone groups. These results indicate that ivermectin has a synergistic effect with gemcitabine in preventing cancer progression and could be a potential antitumor drug for the treatment of pancreatic cancer. Key words: Pancreatic cancer, Gemcitabine, Ivermectin, apoptosis, ROS, mitochondria dysfunction Citation Format: daeun lee, joon seong park, yun sun lee, hyeon woong kang, hyo jung kim. Ivermectin suppresses pancreatic cancer via mitochondria dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2320.
Abstract 2089: Evaluating <i>in vivo</i> efficacy of anti-TSLP antibodies in humanized B-hTSLP/hTSLPR mice
Authors: Shujin Zhang, Yanhui Nie, Jiahui Chang, Veronika Chromikova, Luke (Zhaoxue) Yu, Mari Kuraguchi
Journal: Cancer Research (2022)

Abstract Expression of the epithelial cytokine, thymic stromal lymphopoietin (TSLP), has been observed across several barrier surfaces and plays a critical role in both physiological and pathological processes. Via T helper (Th) 2 cytokine production, TSLP has been implicated in asthma, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, and chronic obstructive pulmonary disease. This range in which TSLP exerts its effects on inflammatory diseases makes the TSLP/TSLPR axis an attractive therapeutic target. At Biocytogen, we generated a novel TSLP/TSLPR double humanized mouse model that enables in vivo assessment of human anti-TSLP and anti-TSLPR antibodies. In our B-hTSLP/hTSLPR mice, the murine Tslp and Tslpr genes are replaced with the human TSLP and TSLPR genes by homologous recombination. ELISA analysis showed that human TSLP (after induction with calcipotriol) was exclusively detectable in homozygous B-hTSLP/hTSLPR mice compared to wild type mice. Similarly, flow cytometry analysis indicated TSLPR expression was detectable in monocytes, neutrophils, macrophages, total DCs, cDC1, cDC2, Mo-DC and Pre-DC. Percentages of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hTSLP/hTSLPR mice were comparable to those in the wild type mice, demonstrating that introduction of human TSLP and TSLPR in place of their mouse counterparts did not impair the overall development, differentiation, or distribution of these cell types. Furthermore, using an asthma mouse model via induction with ovalbumin (OVA), we showed that an anti-TSLP antibody (Tezepelumab, synthesized in house) was efficacious in controlling asthma progression in B-hTSLP/hTSLPR mice. Altogether, B-hTSLP/hTSLPR mice are a promising model for preclinical in vivo pharmacodynamic assessment of TSLP antibodies. Citation Format: Shujin Zhang, Yanhui Nie, Jiahui Chang, Veronika Chromikova, Luke (Zhaoxue) Yu, Mari Kuraguchi. Evaluating in vivo efficacy of anti-TSLP antibodies in humanized B-hTSLP/hTSLPR mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2089.
Abstract 2095: Selective inhibition of the STAT3 pathway suppresses K-ras mutant lung tumorigenesis
Authors: Michael J. Clowers, Cody Chou, Bo Yuan, Walter V. Velasco, Melody Zarghooni, Stephen Peng, T Kris Eckols, Humam Kadara, David J. Tweardy, Seyed Javad Moghaddam
Journal: Cancer Research (2022)

Abstract K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-drug cancer subtype characterized by a chronic inflammatory tumor microenvironment (TME). Resistance to therapies, including immune checkpoint blockade (ICB), necessitates therapies that target this inflammatory TME. A major transcription factor that mediates chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3). Inhibiting STAT3 may attenuate pro-tumor inflammation. Moreover, STAT3 modulates PD-L1 transcription, so STAT3 inhibitors in conjunction with ICB may increase ICB response rates. Here, we tested the anti-tumor ability of TTI-101, a selective STAT3 inhibitor, in a STAT3 addicted lung cancer cell line (MDA-F471) and in a transgenic mouse model of KM-LUAD (CCSPCre/LSL-KrasG12D, CC-LR). For in vivo experiments, CC-LR mice were treated daily with 50 mg/kg TTI-101 by oral gavage from 10 to 14 weeks of age to model a preventative regimen or from 14 to 18 weeks of age to survey the treatment effect on established tumors. TTI-101 was compared to anti-PD-1 ICB, with 200 μg injected intraperitoneally 3 times per week. In MDA-F471 cells, TTI-101 treatment decreased cell viability, with an IC50 of ~ 20 μM. In mice treated from 10 to 14 weeks of age, TTI-101 therapy significantly reduced the tumor burden compared to ICB. TTI-101 also reduced the number of proliferating cells within tumors. Mice in the 14-18-week group displayed similar trends, but these experiments are ongoing, as are combination TTI-101 and ICB treatment regimens. Our studies show that TTI-101 can reduce K-ras driven tumor cell proliferation in vitro and in vivo, suggesting STAT3 inhibition as an alternative preventive and therapeutic modality for KM-LUAD. The ongoing combination treatments and the 14-18-week cohorts will elucidate the timing of treatments as well as reveal if by targeting the inflammatory TME we are able to improve response to ICB. Funded by: R01 grant from NIH/NCI (R01CA225977) Citation Format: Michael J. Clowers, Cody Chou, Bo Yuan, Walter V. Velasco, Melody Zarghooni, Stephen Peng, T Kris Eckols, Humam Kadara, David J. Tweardy, Seyed Javad Moghaddam. Selective inhibition of the STAT3 pathway suppresses K-ras mutant lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2095.
Abstract 2996: Pre-activation of autophagy impacts PARP inhibitor sensitivity of prostate cancer cells
Authors: Maxime Cahuzac, Benjamin Péant, Hubert Fleury, Anne-Marie Mes-Masson, Fred Saad
Journal: Cancer Research (2022)

Abstract Introduction: Advanced prostate cancer (APC) is one of the most common causes of cancer-related mortality in males largely related to the development of resistance to hormonal and chemotherapeutic based regimens. Recently, the PARP inhibitor (PARPi) olaparib was shown to improve progression-free and overall survival in patients with APC although resistance remains a barrier to cure. Therapeutic resistance in cancers can be mediated by autophagy, a cellular recycling process. Here we addressed the role of autophagy in the development of olaparib resistance in APC. Methods: Autophagy levels and olaparib sensitivity were evaluated in prostate cancer (PC) cell lines (LNCaP, C4-2B and PC-3) by western blots and clonogenic assays, respectively. We introduced a double-tagged (mCherry-GFP) LC3 protein in cells to monitor autophagic flux by confocal microscopy and evaluated the temporal importance of autophagy activation by rapamycin on olaparib sensitivity. We measured cell proliferation (Incucyte), cell cycle (flow cytometry) and DNA repair (microscopy). Finally, we confirmed the role of autophagy in olaparib sensitivity using CRISPR/Cas9 Atg16L1 knockout cell lines. Results: We found a correlation between the basal level of autophagy and olaparib sensitivity in PC cell lines. PC-3 cells were olaparib resistant and had a higher basal level of autophagy compared to LNCaP and C4-2B cells, which were PARPi sensitive. When autophagy was pre-activated before olaparib treatment, PC cell lines became more resistant by increasing homologous recombination activity. This autophagy-mediated resistance was partially regulated by a balance between SQSTM1 and FLNA protein levels in the nucleus. Inhibition of autophagy or post-activated autophagy prevented development of PARPi resistance. Conclusion: The autophagic flux is associated with PARPi resistance in PC cell lines by regulating DNA repair. Inhibiting autophagy may lead to new strategies to increase PARPi efficacy. Understanding the role of autophagy in PC progression may lead to strategies that prevent the development of PARPi resistance. Citation Format: Maxime Cahuzac, Benjamin Péant, Hubert Fleury, Anne-Marie Mes-Masson, Fred Saad. Pre-activation of autophagy impacts PARP inhibitor sensitivity of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2996.